This is a competitive renewal application to investigate the molecular mechanisms of the chemopreventive effect of cancer by tea polyphenols. During the previous funding period, we investigated the effect of tea polyphenols on various protein kinases and AP-1 and NF-kappaB signal transduction pathways in cell culture and genetically-modified mouse models. We found that tea polyphenols (-)-epigallocatechin 3-gallate (EGCG) and theaflavins inhibited tumor promoter-induced or oncogene-induced protein kinases and multiple signal transduction pathways. The dose range of these tea polyphenols that effectively inhibited these signals is similar to that which can inhibit cell transformation and skin carcinogenesis. In this renewal proposal, we hypothesize that Pin-1 acts as a central hub in mediating the anticancer effects of tea polyphenols on multiple signal transduction pathways. This hypothesis is based on our other published data and our preliminary data showing that (a) Pin-1 is critical for neoplastic cell transformation and tumorigenesis; (b) EGCG can bind with Pin-1; (c) EGCG and other tea polyphenols inhibit multiple signal transduction pathways AP-1, NF-kappaB, and NFAT; (d) Pin-1 is one of the core proteins that can regulate all of these distinct signaling pathways. To test this hypothesis, we will use state-of-the-art technologies such as X-ray crystallography, protein chemistry, molecular biology, cell culture and knockout mouse models with the following Specific Aims: Specific Aim 1. To study the role of Pin-1 in the inhibitory activity of EGCG on cell transformation in vitro. Specific Aim 2. To study the interactions of EGCG and other tea polyphenols with Pin-1. Specific Aim 3. To study the role of Pin-1 as a molecular target for the anti-tumor effect of EGCG in vivo in a tumor xenograft model. We have established experimental conditions through preliminary investigations and expect that the proposed molecular mechanism studies will lead to development of better chemopreventive agents and facilitate the design of more effective chemoprevention trials. PUBLIC HEALTH RELEVANCE Many studies have shown the anti-cancer effect of drinking green and black tea in both laboratory studies and human population studies. However, the mechanisms of the anti-cancer effect of tea are not clear. This study is to identify the molecular mechanisms/targets associated with the anti-cancer effects exhibited by tea. Such knowledge will help to develop better cancer preventing agens and design more effective cancer prevention trials.